The present disclosure generally related to an improved process for the preparation of various piperidine derivatives. More particularly, the present disclosure related to an improved process for preparing sufentanil base (1) and related compounds, which advantageously utilizes more cost effective and/or less hazardous reagents, as well as eliminates the need for expensive and/or time consuming purification techniques.

Sufentanil citrate, the citrate salt of Sufentanil (1), was first reported by Niemegeers et al (Arzneim. Forsch. 26:1551-1556, 1976). It is a piperidine derivative and a member of a series of potent fentanyl analogues. It is a powerful analgesic with an excellent safety margin as compared to other narcotic agents. It is furthermore characterized by a high selectivity and affinity (approximately 10 times greater than fentanyl) for “mu” opiate receptors. Sufentanil citrate produces, unlike fentanyl or morphine, complete anesthesia with minimal side-effects. When compared with fentanyl, its pharmacokinetic profile in humans shows a smaller volume of distribution, resulting in a terminal half-life intermediate between alfentanil and fentanyl. Sufentanil citrate, in high doses with 100% oxygen in patients undergoing major surgical procedures, produces excellent cardiovascular stability and preserves cardiac output and myocardial oxygen balance with minimal changes in heart rate. Sufentanil citrate suppresses most hormonal responses to surgical stimulation, without producing significant cardiovascular depression. Additionally, sufentanil citrate, like fentanyl, does not cause histamine release.
In low to moderate doses, sufentanil citrate may have further advantages over other narcotic agents. For example, when compared with meperidine, morphine and fentanyl in patients undergoing general surgery under balanced anesthesia, sufentanil citrate provides stable cardiovascular parameters, low preoperative catecholamine plasma levels, very little need for additional inhalation supplementation, and a low incidence of postoperative respiratory depression. Because of its remarkably low cardiovascular toxicity, sufentanil citrate has been evaluated as a total intravenous anesthetic for major surgical procedures. It is primarily used for open heart surgery and major operations in patients with severe cardiovascular compromise.
The chemical name for sufentanil citrate is N[4-(methoxymethyl)-1[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate, and it has an empirical formula of C28H38N2O9S. Sufentanil citrate is a white crystalline powder (molecular weight approximately 578.7 g) with a reported melting point of approximately 136.3° C. Additionally, it is soluble in most alcohols.
Synthesis of sufentanil base (1) is disclosed, for example, in U.S. Pat. No. 3,998,834 (to Janssen). The process described therein, however, is somewhat lengthy and complicated. Improved procedures were published in U.S. Pat. Nos. 5,489,689 (to Mathew) and 7,208,604 (to Mathew et al.); however, these procedures contain steps that are problematic to scale-up, such as chromatography with diethyl ether, the use of flammable reagents (e.g., 95 wt % sodium hydride dispersion), and/or the use of reagents that are the expensive and difficult to acquire in large quantities (e.g., 15-crown-5 ether as a reaction co-solvent). Accordingly, there continues to be a need for an improved procedure for the preparation of the synthetic opioid, sufentanil, as well as other related compounds. Preferably, such an improved process would be more cost effective, and/or safer to perform, particularly on a production scale, than currently used processes.